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Noggin null allele mice exhibit a microform of holoprosencephaly


Lana-Elola, E; Tylzanowski, P; Takatalo, M; Alakurtti, K; Veistinen, L; Mitsiadis, T A; Graf, D; Rice, R; Luyten, F P; Rice, D P (2011). Noggin null allele mice exhibit a microform of holoprosencephaly. Human Molecular Genetics, 20(20):4005-4015.

Abstract

Holoprosencephaly (HPE) is a heterogeneous craniofacial and neural developmental anomaly characterized in its most severe form by the failure of the forebrain to divide. In humans, HPE is associated with disruption of Sonic hedgehog and Nodal signaling pathways, but the role of other signaling pathways has not yet been determined. In this study, we analyzed mice which, due to the lack of the Bmp antagonist Noggin, exhibit elevated Bmp signaling. Noggin(-/-) mice exhibited a solitary median maxillary incisor that developed from a single dental placode, early midfacial narrowing as well as abnormalities in the developing hyoid bone, pituitary gland and vomeronasal organ. In Noggin(-/-) mice, the expression domains of Shh, as well as the Shh target genes Ptch1 and Gli1, were reduced in the frontonasal region at key stages of early facial development. Using E10.5 facial cultures, we show that excessive BMP4 results in reduced Fgf8 and Ptch1 expression. These data suggest that increased Bmp signaling in Noggin(-/-) mice results in downregulation of the hedgehog pathway at a critical stage when the midline craniofacial structures are developing, which leads to a phenotype consistent with a microform of HPE.

Abstract

Holoprosencephaly (HPE) is a heterogeneous craniofacial and neural developmental anomaly characterized in its most severe form by the failure of the forebrain to divide. In humans, HPE is associated with disruption of Sonic hedgehog and Nodal signaling pathways, but the role of other signaling pathways has not yet been determined. In this study, we analyzed mice which, due to the lack of the Bmp antagonist Noggin, exhibit elevated Bmp signaling. Noggin(-/-) mice exhibited a solitary median maxillary incisor that developed from a single dental placode, early midfacial narrowing as well as abnormalities in the developing hyoid bone, pituitary gland and vomeronasal organ. In Noggin(-/-) mice, the expression domains of Shh, as well as the Shh target genes Ptch1 and Gli1, were reduced in the frontonasal region at key stages of early facial development. Using E10.5 facial cultures, we show that excessive BMP4 results in reduced Fgf8 and Ptch1 expression. These data suggest that increased Bmp signaling in Noggin(-/-) mice results in downregulation of the hedgehog pathway at a critical stage when the midline craniofacial structures are developing, which leads to a phenotype consistent with a microform of HPE.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > Center for Dental Medicine > Institute of Oral Biology
Dewey Decimal Classification:610 Medicine & health
Language:English
Date:5 August 2011
Deposited On:28 Oct 2011 13:00
Last Modified:26 Jul 2018 16:03
Publisher:Oxford University Press
ISSN:0964-6906
Additional Information:This is a pre-copy-editing, author-produced PDF of an article accepted for publication in Human Molecular Genetics following peer review. The definitive publisher-authenticated version "Lana-Elola, E; Tylzanowski, P; Takatalo , M; Alakurtti, K; Veistinen, L; Mitsiadis, T A; Graf, D; Rice, R; Luyten, F P; Rice, D P C (2011). Noggin null allele mice exhibit a microform of holoprosencephaly. Human Molecular Genetics, 20(20):4005-4015." is available online at: 10.1093/hmg/ddr329
OA Status:Green
Publisher DOI:https://doi.org/10.1093/hmg/ddr329
PubMed ID:21821669

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